FUNCTIONAL EFFECTS OF DIET INDUCED OBESITY ON PERMEABLIZED RAT MUSCLE FIBRES

INTRODUCTION Muscle performance is determined by the metabolic, calcium handling, and sarcomeric characteristics of its constituent fibres. Diet induced obesity (DIO) may influence contractile performance in whole muscle, but little is known about the effects of DIO at the single fibre level. Particularly, how DIO might influence the contractile characteristics of single fibres free from the influence of metabolic or calcium handling properties is not established. There is some limited evidence to suggest that DIO may influence the sarcomeric proteins. For example, troponin T, an important regulatory protein found on the thin filament, exhibits a shift from the fast T3 isoform, to the slow T1 isoform, in mouse soleus muscle following high fat feeding, with no associated change in myosin heavy chain isoform [1]. These results suggest that DIO may cause fast fibres to express slow isoforms of sarcomeric proteins in postural muscles of mixed fibre-type. The purpose of this study was to assess the force-calcium and force-velocity relationships of skinned fast and slow fibres of vastus intermedius, a mixed fibre-type postural muscle [2], in chow-fed rats and a rat model of DIO. It was hypothesized that fast fibres from DIO rats would exhibit characteristics associated with a slower fibre phenotype, including increased calcium sensitivity and lower shortening velocities. METHODS Individually housed male Sprague-Dawley rats, aged 10-12 weeks, were randomized to undergo diet induced obesity (DIO) where they were fed a high fat, high sugar diet (n = 6) or a standard chow diet (n = 6) for 12 weeks. The caloric content of DIO diets was 40% fat and 45% sucrose, compared to chow diets which consisted of 12% fat and 0% sucrose. Both vastus intermedius muscles were collected from each rat. Similar to the mouse soleus, the fibre type distribution of rat vastus intermedius is approximately 50% type I and 50% type IIa fibres [2]. Muscles were chemically skinned in a glycerol-rigor solution for 2 weeks.  Two fast and two slow fibres per animal were then isolated and mounted in a model 802B skinned fibre test system (Aurora Scientific) at 2.4 µm sarcomere length for testing.  Preliminary fibre type assessment was made using a strontium sensitivity test [3].  The force-pCa relationship was assessed from pCa 7.2 to pCa 4.2. The force-velocity relationship was assessed by measuring the shortening velocity during isotonic contractions.  Maximal shortening velocity (Vmax) was assessed by a slack test protocol. Statistical differences were determined using Student’s t-test or a two-way factorial ANOVA and Newman-Keuls post-hoc analysis as appropriate, α = 0.05. RESULTS Dual-energy X-ray absorptiometry scans revealed DIO rats had significantly higher body mass, fat mass, and greater percent body fat than chow fed rats (all p<0.05), while lean mass was not significantly different between groups. DIO did not affect the force per cross-sectional area (CSA) of skinned fibres (Table 1). Fast DIO fibres had significantly lower maximum shortening velocities when compared to fast chow fibres (p<0.05; Table 1). No such differences were observed in slow fibres. Independent of fibre type, DIO fibres had significantly higher calcium sensitivity than chow fibres (p<0.01, Table 1).  While the Hill coefficient of the force pCa relationship was different between fast and slow chow fibres, no differences were seen in DIO fibres (p<0.05; Table 1).DISCUSSION AND CONCLUSIONS Consistent with a fast to slow phenotype transition, Vmax was lower in fast DIO fibres. However, DIO influenced the force-calcium relationship of both fast and slow fibres. Therefore, adaptations are not limited to fast fibres, but rather influence contractility on a larger scale. Whether this influence is global or localized to postural muscles remains to be determined. The specific isoforms of contractile proteins expressed in single fibres should be assessed following DIO

Baryon Binding Energy in Sakai-Sugimoto Model

The binding energy of baryon has been studied in the dual $AdS_5\times S^5$ string theory with a black hole interior. In this picture baryon is constructed of a $D_5$ brane vertex wrapping on $S^5$ and $N_c$ fundamental strings connected to it. Here, we calculate the baryon binding energy in Sakai-Sugimoto model with a $D_4/D_8/\bar{D_8}$ in which the supersymmetry is completely broken. Also we check the $T$ dependence of the baryon binding energy. We believe that this model represents an accurate description of baryons due to the existence of Chern-Simones coupling with the gauge field on the brane. We obtain an analytical expression for the baryon binding energy . In that case we plot the baryon binding energy in terms of radial coordinate. Then by using the binding energy diagram, we determine the stability range for baryon configuration. And also the position and energy of the stable equilibrium point is obtained by the corresponding diagram. Also we plot the baryon binding energy in terms of temperature and estimate a critical temperature in which the baryon would be dissociated.Comment: 14 pages, 1 fi

Circadian influences on myocardial infarction

Components of circadian rhythm maintenance, or “clock genes,� are endogenous entrainable oscillations of about 24 h that regulate biological processes and are found in the suprachaismatic nucleus (SCN) and many peripheral tissues, including the heart. They are influenced by external cues, or Zeitgebers, such as light and heat, and can influence such diverse phenomena as cytokine expression immune cells, metabolic activity of cardiac myocytes, and vasodilator regulation by vascular endothelial cells. While it is known that the central master clock in the SCN synchronizes peripheral physiologic rhythms, the mechanisms by which the information is transmitted are complex and may include hormonal, metabolic, and neuronal inputs. Whether circadian patterns are causally related to the observed periodicity of events, or whether they are simply epi-phenomena is not well established, but a few studies suggest that the circadian effects likely are real in their impact on myocardial infarct incidence. Cycle disturbances may be harbingers of predisposition and subsequent response to acute and chronic cardiac injury, and identifying the complex interactions of circadian rhythms and myocardial infarction may provide insights into possible preventative and therapeutic strategies for susceptible populations.ECU Open Access Publishing Support Fun

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe